Excessive uterine bleeding, menorrhagia, is one of the most common reasons for gynecology referral in pre-menopausal women. Although medical therapy is generally the first approach, many women will eventually require a hysterectomy. Hysterectomy is associated with a significant in-patient hospital stay and a period of convalescence that makes it an unattractive and unnecessarily invasive option for many women. Hysteroscopic endometrial ablation or resection, and more recently “second generation” devices such as balloon or microwave ablation offer a day-case surgical alternative to hysterectomy for these women. These methods are also cheaper procedures than hysterectomy. Hysterectomy guarantees amenorrhea, but is costly and has a significant impact on health-related quality of life immediately after surgery.
Complete endometrial removal or destruction is one of the most important determinants of treatment success. Therefore endometrial ablation will be most effective if undertaken in the immediate post-menstrual phase when endometrial thickness is usually thin (<four mm), the thickness most methods of endometrial ablation are effective in destroying. However there are often difficulties in reliably arranging surgery for this time.
During the menstrual cycle endometrial thickness varies from as little as one mm in the immediate postmenstrual phase to ten mm or more in the late secretary phase. The radius of a standard electrosurgery loop used for endometrial resection is about four mm and the depth of tissue destruction with Nd:YAG laser or a roller ball electrode is four to six mm. With these depths of tissue removal or destruction, it is apparent that surgery will be most effective if undertaken when endometrial thickness is less than 4 mm, either in the immediate post-menstrual phase or following the administration of hormonal agents which induce endometrial thinning or atrophy.
The proportion of women who experience amenorrhea following endometrial ablation varies in different series from 30 to 60%; though the proportion experiencing an improvement in menstrual symptoms is considerably higher.
Difficulty in reliably arranging surgery in the immediate post-menstrual phase and the unpredictable thickness of the unprepared endometrium has resulted in much attention being given to the use of endometrial thinning agents prior to surgery. A number of randomized studies have now been undertaken comparing different hormonal agents with each other or with no pre-operative treatment or placebo. The most commonly evaluated agents have been gonadotropin-releasing hormone (GnRH) agonists and danazol. Progestogens have also been studied.
It has been suggested that the use of these agents, particularly GnRH analogues, will reduce operating time, improve the intra-uterine operating environment, and reduce distension medium absorption. It is also possible that their use may also improve post-operative outcome. An improved operating environment might also reduce the rate of complications associated with these procedures. An improvement in post-operative outcome might increase patient satisfaction and reduce the proportion of women undergoing subsequent hysterectomy. However, these agents do add significant additional cost to any hysteroscopic procedure.
Cost would be one factor that would make the use of progestogens attractive, as they are significantly cheaper than both GnRH analogues and danazol. In a small, randomized study evaluating the effect of progestogens on endometrial thickness alone, norethisterone and medroxyprogesterone acetate had no effect on endometrial thickness, though cyproterone acetate did produce a significant reduction in endometrial thickness in an amount similar to danazol. Observational studies that have included patients treated with different progestogens have reported disappointing effects.
In a recent review article directed to the agents used for endometrial thinning before endometrial ablation, the authors found that when compared with no treatment, GnRH analogues are associated with a shorter duration of surgery, greater ease of surgery, and a higher rate of post-operative amenorrhea at 12 months with hysteroscopic resection or ablation. Post-operative dysmenorrhea also appears to be reduced. However, the use of GnRH analogues was found to have no effect on intra-operative complication rates and patient satisfaction with this surgery. This is because of the high satisfaction rate irrespective of the use of any pre-operative endometrial-thinning agents. GnRH analogues were found to produce more consistent endometrial atrophy than danazol. Both GnRH analogues and danazol produced side effects in a significant proportion of women, though few studies have reported these in detail. Few randomized data are available to assess the effectiveness of progestogens as endometrial thinning agents. The effect of any thinning agent on longer-term results is less certain, but where reported, the effect of endometrial thinning agents on benefits such as post-operative amenorrhea appears to reduce with time.
The reviewers concluded that endometrial thinning prior to hysteroscopic surgery in the early proliferative phase of the menstrual cycle for menorrhagia improves both the operating conditions for the surgeon and short-term post-operative outcome. Gonadotropin-releasing hormone analogues produce slightly more consistent endometrial thinning than danazol, though both agents produce satisfactory results. The effect of these agents on longer-term post-operative outcomes such as amenorrhea and the need for further surgical intervention reduces with time. If progestogens are to be used at all it should only be within the context of a trial to formally evaluate them.
There is, therefore, a need for less expensive agents for endometrial thinning prior to endometrial ablation or other surgical procedures on the endometrial cavity and uterus.
Human endometrium is a unique tissue that undergoes sequential phases of proliferation, and secretory changes followed by tissue shedding and bleeding during menstruation. Proliferation of the endometrial cells occurs in response to estrogen stimulation particularly during the first half of the menstrual cycle (follicular or proliferative phase). Menstruation is the process by which the endometrium is discarded each month if pregnancy fails to occur. It involves sloughing of the endometrium over a period of days, bleeding and subsequent repair. Work carried out in the 1930s established that ovarian steroids, estrogen and progesterone, were responsible for the changes in endometrial structure and function throughout the cycle.
Within the uterus, the female sex steroids estrogen and progesterone play pivotal roles in endometrial development. More specifically, these steroids regulate a multitude of cellular processes, which include cell proliferation and differentiation, as well as regulation of vascular permeability, angiogenesis and adenogenesis. To bring about these changes, estrogen and progesterone must appropriately modulate a variety of factors, which include growth factors, cytokines, extracellular matrix proteins and adhesion molecules.
Steroids interact with their target organs via specific nuclear receptors. The expression of endometrial sex steroid receptors (progesterone receptor (PR), oestrogen receptor (ER), androgen receptor (AR), all of which are nuclear proteins, varies both temporally and spatially across the menstrual cycle. The expression of ER and PR are under dual control of estrogen and progesterone. Both endometrial ER and PR are up-regulated during the follicular phase by ovarian estrogen and subsequently down regulated in the luteal phase by progesterone acting at both the transcriptional and the post-transcriptional levels. Experiments with rhesus macaques that have been treated with oestrogen and progesterone indicate that the induction of menstruation is identical under the following two conditions: withdrawal of progesterone alone while estrogen is maintained, or withdrawal of both estrogen and progesterone. Furthermore, the administration of the antiprogestin, mifepristone (RU486) is associated with marked endometrial ECM breakdown and excessive menstrual bleeding.
Aromatase is a microsomal member of the cytochrome P450 hemoprotein-containing enzyme complex superfamily (P450arom, the product of the CYP19 gene) that catalyzes the rate-limiting step in the production of estrogens, that is, the conversion of androstenedione and testosterone via three hydroxylation steps to estrone and estradiol respectively. Aromatase activity is present in many tissues, such as the ovaries, the brain, adipose tissue, muscle, liver, breast tissue, and in malignant breast tumors. The main sources of circulating estrogens are the ovaries in premenopausal women and adipose tissue in postmenopausal women.
Aromatase is a good target for selective inhibition because estrogen production is a terminal step in the biosynthetic sequence. A large number of aromatase inhibitors have been developed and utilized in clinical studies over the last 20 years, mainly for treatment of breast cancer.
The first aromatase inhibitor to be used clinically was aminoglutethimide, which induces a medical adrenalectomy by inhibiting many other enzymes involved in steroid biosynthesis. Although aminoglutethimide is an effective hormonal agent in postmenopausal breast cancer, its use is complicated by the need for concurrent corticosteroid replacement. In addition side effects, like lethargy, rashes, nausea and fever, result in 8-15% of patients stopping the aminioglutethimide treatment. The lack of specificity and unfavorable toxicity profile of aminoglutethimide has led to a search for more specific aromatase inhibitors. In addition, the earlier aromatase inhibitors were not able to completely inhibit aromatase activity in premenopausal patients. Therefore, aromatase inhibitors have been primarily used for postmenopausal patients.
Aromatase inhibitors have been classified in a number of different ways, including first-, second-, and third-generation; steroidal and nonsteroidal; and by binding activity, i.e., reversible (ionic binding) and irreversible (suicide inhibitor, covalent binding). The most successful, third generation aromatase inhibitors are now available commercially for breast cancer treatment.
The commercially available agents include two nonsteroidal preparations, anastrozole and letrozole, and a steroidal agent, exemestane. Exemestane is available from Pfizer Inc., New York, N.Y. under the trademark Aromasin®; Anastrozole, is available from AstraZeneca under the trademark Arimidex® (ZN 1033); and letrozole is available from Novartis Pharmaceutical Corporation under the trademark Femara® CGS 20267). Anastrozole and letrozole are selective aromatase inhibitors, available for clinical use in North America, Europe and other parts of the world for treatment of postmenopausal breast cancer. These triazole (antifungal) derivatives are reversible, competitive aromatase inhibitors, which are highly potent and selective. Their intrinsic potency is considerably greater than that of aminoglutethimide, and at doses of 1-5 mg/day, they inhibit estrogen levels by 97% to >99%. This level of aromatase inhibition results in estradiol concentrations below detection by most sensitive immunoassays. The high affinity of aromatase inhibitors for aromatase is thought to reside in the −4 nitrogen of the triazole ring that coordinates with the heme iron atom of the aromatase enzyme complex. Aromatase inhibitors are completely absorbed after oral administration with mean terminal t1/2 of approximately 45 hr (range, 30-60 hr). They are cleared from the systemic circulation mainly by the liver. Gastrointestinal disturbances account for most of the adverse events, although these have seldom limited therapy. Other adverse effects are asthenia, hot flashes, headache, and back pain.
The wide clinical safety of aromatase inhibitors, as well as the reduced cost of treatment, make these agents promising for use in treatment modalities for estrogen-dependant disorders, e.g., endometriosis and uterine fibroids. Although these agents are mainly used in postmenopausal women, most recently, we have reported the success of these agents in inhibiting estrogen production in women of the reproductive age group. Mitwally, et al., Aromatase Inhibition: A novel method of ovulation induction in women with polycystic ovarian syndrome, Reprod. Technol., Vol. 10, No. 5, pages 244-247 (2000); Mitwally, et al., Use of an aromatase inhibitor for induction of ovulation in patients with an inadequate response to clomiphene citrate, Fertil. Steril., Vol. 75, No. 2, 305-9 (2001); and Mitwally, et al., Aromatase inhibition improves ovarian response to FSH: A potential option for low responders during ovarian stimulation, Fertil. Steril., Vol. 77, No. 4, pages 776-80 (2002).
Expression of the aromatase enzyme has been found in the endometrium in association with different estrogen disorders such as endometriosis and uterine fibroids. An “intracrine” effect of estrogen in these disorders has been suggested. Estrogen produced by local aromatase activity can exert its effects by readily binding to its nuclear receptor within the same cell. Disease-free endometrium and myometrium, on the other hand, lack aromatase expression. Therefore, we propose to use an aromatase inhibitor to cause thinning of the endometrium by decreasing estrogen production during the pre-operative period before endometrial ablation.